Dopamine plays a role in multiple physiological processes ranging from movement and reward to the regulation of hormonal balance. Dopamine receptor agonists or antagonists are used for the treatment of diseases such as schizophrenia, depression, attention deficit disorder, and Parkinson's disease. Recent work also indicates that the altered regulation of dopamine release induced by many drugs of abuse plays a critical role in early processes linked to early aspects of addiction. This there is a considerable understanding of the physiological role of dopamine in the central nervous system. There is likewise an enormous literature on molecular and biochemical aspects of dopamine signaling. Studies range from, the expression of the multiple is forms of dopamine receptors and second messenger cascades in cell lines to, biochemical and electrophysiological examination of the actions of dopamine and receptor agonists on neurons in various parts of the central nervous system. Thus the signaling cascades that are activated by dopamine receptors are well characterized. In spite of the wealth of knowledge of the dopamine system, little has been done on the actions of synaptically released dopamine at the cellular level. This hole in knowledge is not for the lack of effort, but lies in the fact that robust physiological detectors linked to dopamine synapses have been difficult to find in the major projection areas. This proposal uses recordings from dopamine neurons in brain slices from mouse to (1) define the inhibitory synaptic potential (IPSP) that results from the dendritic release of dopamine, (2) identify the presynaptic mechanism(s) and sites of dendritic dopamine release and (3) determine how the dendritic release of dopamine is altered following the induction of excitatory synaptic plasticity resulting from the treatment of animals with cocaine. The robust connection between the dendritic release of dopamine and the activation of an IPSC remains the best and probably only site at which dopamine transmission has been directly examined. The results of this study will therefore form a connection between knowledge at molecular and systems levels. The characterization of the synaptic mechanisms that determine rise and fall of extracellular dopamine in combination with a physiological response, will add considerably to the decades long search for an understanding of the role of dopamine in health and disease. PUBLIC HEALTH RELEVANCE: Dopamine agonists and antagonists are used clinically for the treatment of a number of diseases pointing out the importance of a complete understanding of the cellular and synaptic processes mediated by this important transmitter. The results from this study will define the cellular interactions between endogenously released dopamine and the receptors that detect the release of dopamine. From this work knowledge of dopamine-dependent transmission in many areas of the brain will be facilitated and lead to a better understanding of the disruptions in transmission in many diseases including addiction.